...part 2.
Effects of Intermittent Fasting on Health and Aging
Until recently, studies of caloric restriction and intermittent fasting focused on aging and the life span. After nearly a century of research on caloric restriction in animals, the overall conclusion was that reduced food intake robustly increases the life span.
In one of the earliest studies of intermittent fasting, Goodrick and colleagues reported that the average life span of rats is increased by up to 80% when they are maintained on a regimen of alternate-day feeding, started when they are young adults. However, the magnitude of the effects of caloric restriction on the health span and life span varies and can be influenced by sex, diet, age, and genetic factors.
7 A meta-analysis of data available from 1934 to 2012 showed that caloric restriction increases the median life span by 14 to 45% in rats but by only 4 to 27% in mice. A study of 41 recombinant inbred strains of mice showed wide variation, ranging from a substantially extended life span to a shortened life span, depending on the strain and sex. However, the study used only one caloric-restriction regimen (40% restriction) and did not evaluate health indicators, causes of death, or underlying mechanisms. There was an inverse relationship between adiposity reduction and life span suggesting that animals with a shortened life span had a greater reduction in adiposity and transitioned more rapidly to starvation when subjected to such severe caloric restriction, whereas animals with an extended life span had the least reduction in fat.
The discrepant results of two landmark studies in monkeys challenged the link between health-span extension and life-span extension with caloric restriction. One of the studies, at the University of Wisconsin, showed a positive effect of caloric restriction on both health and survival, whereas the other study, at the National Institute on Aging, showed no significant reduction in mortality, despite clear improvements in overall health. Differences in the daily caloric intake, onset of the intervention, diet composition, feeding protocols, sex, and genetic background may explain the differential effects of caloric restriction on life span in the two studies.
In humans, intermittent-fasting interventions ameliorate obesity, insulin resistance, dyslipidemia, hypertension, and inflammation. Intermittent fasting seems to confer health benefits to a greater extent than can be attributed just to a reduction in caloric intake. In one trial, 16 healthy participants assigned to a regimen of alternate-day fasting for 22 days lost 2.5% of their initial weight and 4% of fat mass, with a 57% decrease in fasting insulin levels.
34 In two other trials, overweight women (approximately 100 women in each trial) were assigned to either a 5:2 intermittent-fasting regimen or a 25% reduction in daily caloric intake. The women in the two groups lost the same amount of weight during the 6-month period, but those in the group assigned to 5:2 intermittent fasting had a greater increase in insulin sensitivity and a larger reduction in waist circumference.
Physical and Cognitive Effects of Intermittent Fasting
In animals and humans, physical function is improved with intermittent fasting. For example, despite having similar body weight, mice maintained on alternate-day fasting have better running endurance than mice that have unlimited access to food. Balance and coordination are also improved in animals on daily time-restricted feeding or alternate-day fasting regimens. Young men who fast daily for 16 hours lose fat while maintaining muscle mass during 2 months of resistance training.
Studies in animals show that intermittent fasting enhances cognition in multiple domains, including spatial memory, associative memory, and working memory; alternate-day fasting and daily caloric restriction reverse the adverse effects of obesity, diabetes, and neuroinflammation on spatial learning and memory.
In a clinical trial, older adults on a short-term regimen of caloric restriction had improved verbal memory. In a study involving overweight adults with mild cognitive impairment, 12 months of caloric restriction led to improvements in verbal memory, executive function, and global cognition. More recently, a large, multicenter, randomized clinical trial showed that 2 years of daily caloric restriction led to a significant improvement in working memory. There is certainly a need to undertake further studies of intermittent fasting and cognition in older people, particularly given the absence of any pharmacologic therapies that influence brain aging and progression of neurodegenerative diseases.
... section on studies of the effect of IF on certain chronic conditions. ...
Practical Considerations
Despite the evidence for the health benefits of intermittent fasting and its applicability to many diseases, there are impediments to the widespread adoption of these eating patterns in the community and by patients. First,
a diet of three meals with snacks every day is so ingrained in our culture that a change in this eating pattern will rarely be contemplated by patients or doctors. The abundance of food and extensive marketing in developed nations are also major hurdles to be overcome.
Second, on switching to an intermittent-fasting regimen, many people will experience hunger, irritability, and a reduced ability to concentrate during periods of food restriction. However, these initial side effects usually disappear within 1 month, and patients should be advised of this fact.
Third, most physicians are not trained to prescribe specific intermittent-fasting interventions. Physicians can advise patients to gradually, over a period of several months, reduce the time window during which they consume food each day, with the goal of fasting for 16 to 18 hours a day. Alternatively, physicians can recommend the 5:2 intermittent-fasting diet, with 900 to 1000 calories consumed 1 day per week for the first month and then 2 days per week for the second month, followed by further reductions to 750 calories 2 days per week for the third month and, ultimately, 500 calories 2 days per week for the fourth month. A dietitian or nutritionist should be consulted to ensure that the nutritional needs of the patient are being met and to provide continued counseling and education. As with all lifestyle interventions, it is important that physicians provide adequate information, ongoing communication and support, and regular positive reinforcement.
Conclusions
Preclinical studies and clinical trials have shown that
intermittent fasting has broad-spectrum benefits for many health conditions, such as obesity, diabetes mellitus, cardiovascular disease, cancers, and neurologic disorders. Animal models show that intermittent fasting improves health throughout the life span, whereas clinical studies have mainly involved relatively short-term interventions, over a period of months. It remains to be determined whether people can maintain intermittent fasting for years and potentially accrue the benefits seen in animal models. Furthermore, clinical studies have focused mainly on overweight young and middle-age adults, and we cannot generalize to other age groups the benefits and safety of intermittent fasting that have been observed in these studies.
Although we do not fully understand the specific mechanisms, the beneficial effects of intermittent fasting involve metabolic switching and cellular stress resistance. However, some people are unable or unwilling to adhere to an intermittent-fasting regimen.
By further understanding the processes that link intermittent fasting with broad health benefits, we may be able to develop targeted pharmacologic therapies that mimic the effects of intermittent fasting without the need to substantially alter feeding habits.
Studies of the mechanisms of caloric restriction and intermittent fasting in animal models have led to the development and testing of pharmacologic interventions that mimic the health and disease-modifying benefits of intermittent fasting. Examples include agents that impose a mild metabolic challenge (2-deoxyglucose, metformin, and mitochondrial-uncoupling agents), bolster mitochondrial bioenergetics (ketone ester or nicotinamide riboside), or inhibit the mTOR pathway (sirolimus).
However, the available data from animal models suggest that the safety and efficacy of such pharmacologic approaches are likely to be inferior to those of intermittent fasting.